4-Aryl-6-amino-3,4-dihydropyrid-2-one-3,5-dicarboxylic acid ester

ABSTRACT

3,4-Dihydropyridones of the formula   wherein R3 is as above defined. These compounds are useful as coronary agents and as anti-hypertensive agents.   wherein R is alkyl, alkenyl or alkynyl, and R1 and R2 are as above defined, with an amidine of the formula   WHEREIN R1 is hydrogen, straight or branched chain alkyl, or COOR&#39;&#39; wherein R&#39;&#39; is a straight, branched or cyclic, saturated or unsaturated hydrocarbon or said hydrocarbon interrupted by 1 or 2 oxygen atoms; R2 is a straight, branched or cyclic, saturated or unsaturated hydrocarbon, aryl unsubstituted or substituted by 1 to 3 of the same or different substituents selected from the group consisting of alkyl, alkoxy, halogen, nitro, cyano, trifluoromethyl, carbalkoxy and SOn-alkyl wherein n is 0, 1 or 2, or naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, thenyl, furyl or pyrryl unsubstituted or substituted by 1 or more substituents selected from the group consisting of alkyl, alkoxy and halogen; and R3 is a straight or branched chain hydrocarbon or said hydrocarbon interrupted by 1 or 2 oxygen atoms, are produced by reacting an Alpha , Beta -unsaturated carboxylic acid ester of the formula

United States Patent [1 1 Meyer et a1.

[ 4-ARYL-6-AMINO-3,4-DlHYDROPYRlD-2- ONE-3,5-D1CARBOXYLIC ACID ESTER [75] Inventors: Horst Meyer; Friedrich Bossert, both of Wuppertai; Wulf Vater, Opladen; Kurt Stoepel, Wuppertal, all of Germany [73] Assignee: Bayer Aktiengesellschaft, Germany [22] Filed: Aug. 21, 1973 [21} Appl. No.: 390,193

[30] Foreign Application Priority Data Aug, 31, 1972 Germany 4, 2242787 [52] US. Cl. 260/2943 G; 260/2564 R;

[56] References Cited UNITED STATES PATENTS 3,708,489 1/1973 Rucker et a1 r r v 260/2955 R 3,773,773 11/1973 Bossert i 4 r r U 260/2955 R 3,775,422 11/1973 Bossert et a1, 4. 260/2949 Primary ExaminerAlan LY Rotman [57] ABSTRACT 3,4-Dihydropyridones of the formula Dec. 9, 1975 a 12 R 000 H R (I) H N ll wherein R is hydrogen, straight or branched chain alky], or COOR' wherein R is a straight, branched or cyclic, saturated or unsaturated hydrocarbon or said hydrocarbon interrupted by l or 2 oxygen atoms; R is a straight, branched or cyclic, saturated or unsaturated hydrocarbon, aryl unsubstituted or substituted by 1 to 3 of the same or different substituents selected from the group consisting of alkyl, alkoxy, halogen, nitro, cyano, trifluoromethyl, carbalkoxy and SO,,-alkyl wherein n is 0, 1 or 2, or naphthyl. quinolyl, isoquinolyl, pyridyl, pyrimidyl, thenyl, furyl or pyrryl unsubstituted or substituted by l or more substituents selected from the group consisting of alkyl, alkoxy and halogen; and R is a straight or branched chain hydrocarbon or said hydrocarbon interrupted by l or 2 oxy gen atoms, are produced by reacting an afi-unsaturated carboxylic acid ester of the formula wherein R is alkyl, alkenyl or alkynyl, and R' and R are as above defined, with an amidine of the formula wherein R is as above defined. These compounds are useful as coronary agents and as anti-hypertensive agents.

18 Claims, N0 Drawings 4-ARYL-6-AMING-3,4-Dll-lYDROPYRID-2-ONE-3,5-

DICARBOXYLIC ACID ESTER wherein R is hydrogen, straight or branched chain alkyl, especially lower alkyl, or COOR' wherein R is a straight, branched or cyclic, saturated or unsaturated hydrocarbon, especially lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl of 3 to 7 carbon atoms or cycloalkenyl of 3 to 7 carbon atoms, or said hydrocarbon interrupted by l or 2 oxygen atoms, especially lower alkyl, lower allcenyl, lower alkynyl, cycloalkyl of 3 to 7 carbon atoms or cycloalkenyl of 3 to 7 carbon atoms interrupted by l or 2 oxygen atoms; R is a straight, branched or cyclic, saturated or unsaturated hydrocar- 2 A 2"\ 3 2 ca- -cs coon Recon rnr' 2 bon, especially lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl of 3 to 7 carbon atoms or cycloalkenyl of 3 to 7 carbon atoms, aryl, especially phenyl, unsubstituted or substituted by l to 3 of the same or different substituents selected from the group consisting of alkyl, especially lower alkyl, alkoxy, especially lower alkoxy, halogen, nitro, cyano, trifluoromethyl, carbalkoxy, especially carb./lower alkoxy and So -alkyl, especially lower alkyl wherein n is 0, l or 2, or R is naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, thenyl, furyl or pyrryl unsubstituted or substituted by l or more, preferably l or 2, substituents selected from the group conn c ooc sisting of alkyl, especially lower alkyl, alkoxy, especially lower alkoxy and halogen; and R is a straight or branched chain hydrocarbon, especially lower alkyl, lower alkenyl or lower alkynyl or said hydrocarbon interrupted by l or 2 oxygen atoms, especially lower alkyl, lower alkenyl or lower alkynyl interrupted by l or 2 oxygen atoms.

According to the present invention, the 3,4-dihydropyridones of formula I are produced by reacting ar mil-unsaturated carboxylic acid ester of the formula (Ill \COOR wherein R is alkyl, preferably of l to 6 carbon atoms and especially of l to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, and R and R are as above defined, with an amidine of the for mula wherein R is as above defined, and recovering the compound produced.

It is distinctly suprising that according to the reaction of the invention the new compounds are produced in such good yields and in such high purity since from the prior art, one would have expected an addition of the amidine radical to the a,B-unsaturated carbonyl radical to give a dihydropyrimidone IV, in accordance with the following equation:

(compare E. F. Silversmith, J. Org. Chem, 27, 4090 (1962)).

An important advantage of the process according to the invention is that it can give high yields and products CH 6000 1-1 HN of high purity and that it can be carried out as a onestep process with little technical effort, and highly economically.

If, for example, 3-nitrobenzylidenemalonic acid diethyl ester and amidinoacetic acid ethyl ester are employed as the starting components, the course of the process of the invention can be illustrated by the following equation:

0000 a 2 5 T31?- :1 1-1 0 00 H H cooc H 2 2 5 5 2 2 5 m 0 g mr The compounds of the present invention are particularly useful because of their long-lasting coronary dilating action, thereby being useful vasodilators, and also because of their anti-hypertensive acitivty.

According to one embodiment of the present invention, R is hydrogen, straight or branched chain alkyl of l to 4 carbon atoms or -COOR' wherein K is straight or branched chain alkyl of l to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon atoms, straight or branched chain alkynyl of 2 to 4 carbon atoms, cycloalkyl of 3 or 4 carbon atoms, cycloalkenyl of 3 or 4 carbon atoms or straight or branched chain alkyl of l to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon atoms, straight or branched alkynyl of 2 to 4 carbon atoms, cycloalkyl of 3 to 4 carbon atoms or cycloalkenyl of 3 or 4 carbon atoms interrupted by l oxygen atom; R is straight or branched chain alkyl of l to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, straight or branched chain alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkenyl of 3 to 6 carbon atoms, phenyl substituted by l or 2 of the same ore different substituents selected from the group consisting of alkyl of l to 4 carbon atoms, alkoxy of l to 4 carbon atoms, halogen (especially chloro or bromo), nitro, cyano, trifluoromethyl, carbalkoxy of l to 4 carbon atoms in the alkoxy moiety and SO,,--alkyl of l to 4 carbon atoms wherein n is or 2, or R is naphthyl, quinolyl, pyridyl, thenyl or furyl unsubstituted or substituted by l or 2 substituents selected from the group consistig of alkyl of l to 4 carbon atoms, alkoxy of l to 4 carbon atoms and halogen (especially chloro or bromo); and R is lower alkyl or lower alkenyl.

According to another embodiment of the present invention, R is hydrogen, straight or branched chain alkyl of l to 4 carbon atoms or COOR wherein R is straight or branched chain alkyl of l to 4 carbon atoms or straight or branched chain alkenyl of 2 to 4 carbon atoms; R is phenyl unsubstituted or substituted by l or 2 substituents selected from the group consisting of alkyl of l to 4 carbon atoms, alkoxy of l to 4 carbon atoms, chloro, bromo, nitro, cyano, trifluoromethyl and S-alkyl of l to 4 carbon atoms, or R is naphthyl, thenyl, furyl or pyridyl; and R is straight or branched chain alkyl or I to 4 carbon atoms.

According to another embodiment of the present invention, R is hydrogen or -CO0R' wherein R is alkyl of l to 3 carbon atoms or alkenyl of 2 or 3 carbon atoms; R is phenyl; phenyl substituted by chloro, dichloro, methyl methoxy, nitro, trifluoromethyl or thiomethyl; naphthyl; thenyl; or furyl; and R is alkyl of l to 3 carbon atoms.

The a,B-unsaturated carboxylic acid esters of formula ll used according to the invention are already known or can be produced by known methods (Org. Reactions XV, 204 and thereafter (1967)).

Representative a,B-unsaturated carboxylic esters include:

Crotonic acid ethyl ester,

-y,'y-dimethylcrotonic acid ethyl ester,

cinnamic acid ethyl ester,

2'-methoxycinnamic acid ethyl ester,

3'-nitrocinnamic acid ethyl ester,

4'-chlorocinnamic acid ethyl ester, 2'-trifluoromethylcinnamic acid ethyl ester, 2-cyanocinnamic acid methyl ester, benzylidenemalonic acid diethyl ester, ethylidenemalonic acid diethyl ester,

isopropylidenemalonic acid dimethyl ester,

A cyclohexenylidenemalonic acid diethyl ester,

2-nitorbenzylidenemalonic acid dimethyl ester.

. 2'-chlorobenzylidenemalonic acid diallyl ester,

2'-methoxybenzylidenemalonic acid dipropargyl ester,

2'-trifluoromethylben zylidenemalonic acid and diisopropyl ester,

3'-nitrobenzylidenemalonic acid diethyl ester,

2-methylsulphonylbenzylidenemalonic acid dimethyl ester,

2-methylmercaptobenzylidenemalonic acid diethyl ester,

2'-methylbenzylidenemalonic acid diallyl ester,

3'-methylbenzylidenemalonic acid dicyclohexyl ester,

2'-cyanobenzylidenemalonic acid diethyl ester,

3'-nitro-6'-chlorobenzylidenemalonic acid diethyl ester,

2',6-dichlorobenzylidenemalonic acid dimethyl ester,

3 ,4 ,5 -trimethoxybe nzylidenemalonic acid diethyl ester,

(l'-naphthylidene)-malonic acid diethyl ester,

(2'-naphthylidene)-malonic acid dimethyl ester,

(2-methoxy-l '-naphthylidene )-malonic acid diethyl ester,

(4'-bromo-l'-naphthylidene )-malonic acid diisopropyl ester,

(2'-quinolyl)-methylidenemalonic acid diethyl ester,

(3'-quinolyl)-methylidenemalonic acid diethyl ester,

(l'-isoquinolyl)methylidenemalonic acid diethyl es ter,

a-pyridylmethylidenemalonic acid diethyl ester,

a-pyridylmethylidenemalonic acid diallyl ester,

B-pyridylmethylidenemalonic acid dimethyl ester,

-y-pyridylmethylidenemalonic acid diethyl ester,

(4 ',6'-dimethoxy-5 '-p yrimidyl )-methylidenemalon ic acid diethyl ester,

(2'-thenyl)-methylidenemalonic acid diethyl ester,

2'-furfurylidenemalonic acid diallyl ester,

(2'-pyrryl)-methylidenemalonic acid diethyl ester and 3'-carbethoxybenzylidenemalonic acid dimethyl ester.

The amidines of formula III which can be used in the process according to the invention are already known or can be produced by known processes (S. M. McElvain, B. E. Tate, J.A.C.S. 73, 2760 (1951)).

Representative amidines include Amidinoacetic acid methyl ester,

amidinoacetic acid ethyl ester,

amidinoacetic acid n-propyl ester,

amidinoacetic acid isopropyl ester,

amidinoacetic acid propargyl ester,

amidinoacetic acid butyl ester,

amidinoacetic acid B-methoxy-ethyl ester and amidonoacetic acid (aand B-)-ethoxyethyl esters.

The am idines can be employed either in the free form or in the form of their salts (for example hydrohalides). They can be liberated from the salts by means of basic reagents (for example alkali alcoholates).

The reaction in the process of the invention is preferably carried out in an inert organic solvent at a temperature of from about 20 to about 200C preferably at the boiling point of the solvent using substantially equimolar proportions of the reagents.

Any inert organic solvent may be used. Preferably solvents include alcohols (such as methanol, ethanol and propanol), ethers (such as dioxane and diethyl ether), glacial acetic acid, pyridine, dimethylformamide, dimethylsulphoxide and acetonitrile.

The reaction can be carried out under normal pressure but also under elevated pressure. in general, normal pressure is used.

The following types of activity have been demonstrated in in vivo animal experiments:

1. On parenteral, oral and perlingual administration the compounds of the present invention produce a distinct and long-lasting dilation of the coronary vessels. This action on the coronary vessels is intensified by a simultaneous nitrile-like effect of reducing the load on the heart. The compounds influence or modify the heart metabolism in the sense of an energy saving.

2. The compounds of the present invention lower the blood pressure of normotonic and hypertonic animals and can thus be used an anti-hypertensive agents.

3. The excitability of the stimulus formation and excitation conduction system within the heart is lowered, so that an amt-fibrillation action demonstrable at therapeutic doses results.

4. The tone of the smooth muscle of the vessels if greatly reduced under the action of the compounds. This vascular-spasmolytic action can take place in the entire vascular system or can manifest itself more or less isolated in circumscribed vascular regions (such as, for example, the central nervous system).

5. The compounds of the present invention have strongly muscular-spasmolytic actions which manifest themselves on the smooth muscle of the stomach, the intestinal tract, the urogenital tract and the respiratory system.

6. The compounds of the present invention influence the cholesterol level and lipid level of the blood.

The present invention includes pharmaceutical compositions em bodying a compound of the present invention as the active ingredient. The pharmaceutical compositions of the present invention contain a major or minor amount, e.g. from 99.5 to 0.1%, preferably 90 to 0.5%, of the active agent as herein defined in combination with a phannaceutical carrier, the carrier comprising one or more solid, semi-solid or liquid diluent, filler and formulation adjuvant which is non-toxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in dosage unit form; i.e. physically discrete units containing a predetermined amount of the drug corresponding to a fraction or multiple of the dose which is calculated to produce the desired therapeutic response. The dosage units can contain one, two, three, four or more single doses or, alternatively, one-half, third or fourth of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to a predetermined dosage regimen, usually a whole, half, third or quarter of the daily dosage administered once, twice, three or four times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness, generally the dosage for I.V. administration will be from 2.5mg to L8 g, preferably 5 to 900 mg. The preferred oral administration is 25 mg to 9 g, preferably 50 mg to 4.5 g. In each case, the dosage represents the amount of active ingredients to be administered. The daily dosage on I.V. administration is preferably 0.5 to 20 mg/kg. In some instances a sufficient therapeutic effect can be obtained at a lower does while in others, a larger dose will be required.

Oral administration can be effected utilizing solid and liquid dosage unit fonns such as powders, tablets, dragees, capsules, granulates, suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate as for example starch, lactose, sucrose, glucose or mannitol. Sweetening, flavoring, preservative, dispersing and coloring agents can also be present.

Capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets, A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally with a binder such as carboxymethyl cellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as parafiin, a re sorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the resulting imprefectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The medicaments can also be combined with free flowing inert carriers and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous sucrose solution while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters, preservatives, flavor additives such as peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound in a non-toxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium and sterilizing the suspension or solution. Alternatively, a measured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed. An accompanying vial or vehicle can be provided for mixing prior to administration. Non-toxic salts and salt solutions can be added to render the injection isotonic. Stabilizers, preservatives and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in which the compound is admixed with low melting water soluble or insoluble solids such as polyethylene glycol, cocoa butter, higher esters as for example myristyl palmitate, or mixtures thereof.

Topical administration can be effected utilizing solid dosage unit forms such as powders or liquid or semiliquid dosage unit forms such as solutions, suspensions, ointments, pastes, creams and gels. The powders are formulated utilizing such carriers as talc, bentonite, silicic acid, polyamide powder and the like. Liquid and semiliquid formulations can utilize such carriers, in addition to those described above, as polyethylene glycol, vegetable and mineral oils, alcohols such as isopropanol and the like. Other excipients such as emulsifiers, preservatives, colorants, perfumes and the like can also be present. Formulations can also be administered as an aerosol, utilizing the usual propellants such as chlorofluorohydrocarbons. Oral and LV. compositions are preferred.

The coronary action of compounds representative of those of the present invention is shown in Table I:

Table 1 Compound of: Distinctly discernible rise in the oxygen saturation in the coronary sinus Example 2 5 mg/kg iv. Example 7 5 mg/kg iv. Example l2 5 mg/kg iv.

Table ll Blood pressure lowering in high blood pressure rats. mg/kg administered orally.

Compound of:

from 0.3

Exa fnple l2 The following non-limitative fliiibles more partisalarly poli'lt out and define the present invfitioi'li EXAMPLE 1 EXAMPLE 2 c H COOC,H,

Boiling a solution of I58 g of 2'-trifluoromethylbenzylidenemalonic acid diethyl ester and 6.5 g of amidinoacetic acid ethyl ester for 5 hours yielded 4- (2'-trifluoromethylphenyl )-6-amino-3 ,4-dihydropyrid- 2-one-3,5-dicarboxylic acid diethyl ester of melting point 164C (ethanol). Yield 62% of theory.

EXAMPLE 3 cooc, a,

a, N o

Boiling a solution of l4.l g of 2'-chlorobenzylidenemalonic acid diethyl ester and 6.5 g of amidinoacetic acid ethyl ester in I00 ml of ethanol for 4 hours yielded 4-(2'-chlorophenyl)-6-amino-3,4-dihydropyrid-2-one-3,5-dicarboxylic acid diethyl ester of melting point 190C (ethanol). Yield 69% of theory.

EXAMPLE 4 H,C, one

Boiling a solution of 8.8 g of cinnamic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in ml of ethanol for 4 hours yielded 4-phenyl-6-amino-3,4-dihydropyrid-2-one-5-carboxylic acid ethyl ester of melting peim 181C (ethanol). Yield 49% of theory.

EXAMPLE oca, Bic-m coocm,

Heating a solution of 13.9 g of 2'-methoxybenzylidenemalonic acid diethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours yielded 4-(2'-methoxyphenyl)-6-amino-3,4- dihydropyrid-2-one-3,5-dicarboxy1ic acid diethyl ester of melting point 198C (ethanol). Yield 55% of theory.

EXAMPLE 6 coocgz,

Boiling a solution of 15.4 g of 4'-methylmercaptobenzylidenemalonic acid diethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for Boiling a solution of 15.9 g of 2',6'-dichlorobenzylidenemalonic acid diethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 120 ml of ethanol for 4 hours yielded 4-(2,6'-dichlorophenyl)-6-amino-3,4- dihydropyrid-2-one-3,5-dicarboxylic acid diethyl ester of melting point 245 (ethanol/dimethylformamide). Yield 78% of theory.

EXAMPLE 8 a, n a

Heating 14.9 g of l-naphthylidenemalonic acid diethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours yielded 4-(1'-naphthyl)- 6-amino 3,4-dihydropyrid-2-0ne-3,5-dicarboxylic acid 10 diethyl ester of melting point 206C (alcohol). Yield 66% of theory.

EXAMPLE 9 a,c ooc I cooc, a,

Boiling a solution of 13.1 g of 2'-methylbenzylidenemalonic acid diethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours yielded 4-(2'-methy1phenyl)-6-amino-3,4-dihydropyrid-2-one-3,S-dicarboxylic acid diethyl ester of melting point 176C (ethanol). Yield of theory.

EXAMPLE 10 me, ooc cooca, cH=ca,

Heating a solution of 13.0 g of benzylidenemalonic acid diallyl ester and 6.5 g of amidinoacetic acid ethyl ester in ml of ethanol for 4 hours yielded 4-pheny1- 6-amino-3,4-dihydropyrid-2-one-3,S-dicarboxylic acid 3-allyl ester-S-ethyl ester of melting point 156C (ethanol). Yield 59% of theory.

EXAMPLE 1 1 11,0, 0 cooc, a,

Boiling a solution of 12.8 g of (2'-thenyl)- methylidenemalonic acid diethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours yielded 4-(2'-thenyl)-6-amino-3,4-dihydropyrid-2-one-3,5-dicarboxylic acid diethyl ester of melting point 193C (ethanol). Yield 57% of theory.

EXAMPLE 12 a, c, 00 cooc, a,

Heating a solution of 14.7 g of 3'-nitrobenzylidenemalonic acid diethyl ester and 6.5 of amidinoacetic acid ethyl ester in 100 ml of ethailt) l'br 11 4 hours yielded 4-(3'-nitrophenyl)-6-amino-3,4-dihydropyrid-2-one-3.S-dicarboxylic acid dicthyl ester of melting point 197C (ethanol). Yield 82% of theory.

EXAMPLE 13 5 ca, 3,1300 'l-i coocatca,

Boiling a solution of 14.5 g of 2'-methylbenzylidenemalonic acid diisopropyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours yielded 4-(2'-methylphenyl)-6-amino-3,4-dihydropyrid-2-one-3,S-dicarboxylic acid 3-isopropyl ester- S-ethyl ester of melting point 175C (isopropanol). Yield 54% of theory.

EXAMPLE 14 oocrflca,

Heating a solution of 15.8 g of 2'-trifluoromethylbenzylidenemalonic acid dicthyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 100 ml of ethanol for 4 hours yielded 4-(2'-trifluoromethylphenyl)-6- amino-3,4-dihydropyrid-2-one-3,S-dicarboxylic acid 3-ethyl ester-S-isopropyl ester of melting point 169C (isopropanol). Yield 62% of theory.

EXAMPLE I5 a oocntca,

(n,c),aco

EXAMPLE 16 n monocficooqa,

Heating a solution of 11.9 g of (2-furfurylidene)- wherein R is (a) unsubstituted phenyl, (b) phenyl which is monosubstituted by cyano, or carbalkoxy in which alkoxy has from 1 to 4 carbon atoms, (c) phenyl which is monosubstituted by one member or disubstituted by two like or different members selected from the group consisting of alkyl of l to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogeno, nitro, trifluoromethyl and alkylthio of 1 to 4 carbon atoms, (d) naphthyl or (e) naphthyl which is monosubstituted by a member selected from the group consisting of halogeno, alkyl of l to 4 carbon atoms, and alkoxy of l to 4 carbon atoms, and

each of R and R is independently selected from the group consisting of alkyl of l to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms and alkoxyalkyl of 3 to 4 carbon atoms.

2. A compound according to claim 1 wherein R is straight or branched chain alkyl of 1 to 4 carbon atoms or straight or branched chain alkenyl of 2 to 4 carbon atoms;

R is phenyl unsubstituted or substituted by l or 2 substituents selected from the group consisting of alkyl of l to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chloro, bromo, nitro, cyano, trifluoromethyl and S-alkyl of 1 to 4 carbon atoms; or R is naphthyl; and

R is straight or branched chain alkyl of 1 to 4 carbon atoms.

3. A compound according to claim 1 wherein R is alkyl of l to 3 carbon atoms or alkenyl of 2 or 3 carbon atoms;

R is phenyl; phenyl substituted by chloro, dichloro,

methyl, methoxy, nitro, trifluoromethyl or thiomethyl; or naphthyl; and

R is alkyl of l to 3 carbon atoms.

4. A compound according to claim 1 wherein R is phenyl, phenyl monosubstituted by alkyl of l to 4 carbon atoms, alkoxy of l to 4 carbon atoms, chloro, bromo, nitro, cyano, trifluoromethyl or methylthio, or naphthyl.

5. A compound according to claim 1 wherein R is alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms, and R is alkyl of l to 4 carbon atoms.

6. The compound according to claim 1 which is a,c,ooc

7. The compound according to claim 1 which is 8. The compound according to claim 1 which is 9. The compound according to claim 1 which is OCH, cl COOC. H,

10. The compound according to claim 1 which is 11. The compound according to claim 1 which is a, c, ooc cooc a,

a, N g H o 12. The compound according to claim 1 which is 13. The compound according to claim 1 which is H,C ooc cooc, a,

a, n o r n 14. The compound according to claim 1 which is n, c, 00c oocn, ca=cn,

c n am a o 15. The compound according to claim I which is a, C 00 cooc, 1-1,

16. The compound according to claim 1 which is CH, 00 coocmca,

17. The compound according to claim 1 which is or, a n,c, 00 I oocmcn,

18. The compound according to claim 1 which is 

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 wherein R'' is straight or branched chain alkyl of 1 to 4 carbon atoms or straight or branched chain alkenyl of 2 to 4 carbon atoms; R2 is phenyl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chloro, bromo, nitro, cyano, trifluoromethyl and S-alkyl of 1 to 4 carbon atoms; or R2 is naphthyl; and R3 is straight or branched chain alkyl of 1 to 4 carbon atoms.
 3. A compound according to claim 1 wherein R'' is alkyl of 1 to 3 carbon atoms or alkenyl of 2 or 3 carbon atoms; R2 is phenyl; phenyl substituted by chloro, dichloro, methyl, methoxy, nitro, trifluoromethyl or thiomethyl; or naphthyl; and R3 is alkyl of 1 to 3 carbon atoms.
 4. A compound according to claim 1 wherein R2 is phenyl, phenyl monosubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chloro, bromo, nitro, cyano, trifluoromethyl or methylthio, or naphthyl.
 5. A compound according to claim 1 wherein R1 is alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms, and R3 is alkyl of 1 to 4 carbon atoms.
 6. The compound according to claim 1 which is
 7. The compound according to claim 1 which is
 8. The compound according to claim 1 which is
 9. The compound according to claim 1 which is
 10. The compound according to claim 1 which is
 11. The compound according to claim 1 which is
 12. The compound according to claim 1 which is
 13. The compound according to claim 1 which is
 14. The compound according to claim 1 which is
 15. The compound according to claim 1 which is
 16. The compound according to claim 1 which is
 17. The compound according to claim 1 which is
 18. The compound according to claim 1 which is 